These experiments are designed to define, in detail, the structure of small intestinal epithelial junctional complexes in normal and in perturbed states and to relate variations in tight junction structure to mucosal function and permeability. To accomplish these goals electron microscopic, freeze fracture, ionic and macromolecular tracer, and electrophysiological experiments will be conducted in parallel. First, normal primate small intestinal epithelium will be studied and specific attention paid to a) variations of tight junction structure related to individual cell types and b) alterations in tight junction structure related to villus tip extrusion zones. Secondly, two states -hyperosmotic load and bile acid exposure - which appear to produce an increase in mucosal permeability will be studied and tight junction structure will be correlated with epithelial resistance and epithelial permeability to ionic and macromolecular tracers. Lastly, the functional significance of tight junction structural heterogeneity in the small intestinal epithelium will be studied. This will be accomplished by manipulating two of the mucosal compartments which have characteristic tight junction structure and account for a large proportion of the structural heterogeneity in small intesinal tight junctions - crypt cells and goblet cells. To manipulate crypt tight junction structure, crypt mitotic index, which relates to crypt tight junction structure, will be inhibited and accentuated and structural-functional correlations will be made applying the above techniques. Goblet cell mucous release will be synchronized with acetylcholine to investigate the effect that the state of mucous release has on goblet cell tight junction structure, and the functional significance will be determined using tracer and electrophysiological techniques. These experiments, designed to correlate tight junction structure in normal and abnormal states with mucosal permeability, may yield insights into small intestinal epithelial function.